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Modeling Activation of Inflammatory Response System

Zurich Normative Study of Rheumatoid Arthritis

To investigate the extent to which the patients’ genetically influenced inflammatory response can be quantified and linked to vulnerability to psychiatric disorders, we have carried out a normative study on a sufficiently large population ascertained trough index cases with a diagnosis of RA. This population was chosen, because (1) there is only a moderate overlap with psychiatric disorders, in the range of 15-25%; (2) a genetic predisposition to RA is well-established, so that a substantial number of subjects with elevated rheumatoid factor IgM can be expected; (3) IgM is in use as a standard diagnostic test for RA, but possesses a low specificity, in the range of 40-50% with a high rate of false-positives due to other causes; and (4) IgM antibodies typically appear early in the course of an infection and do not reappear after further exposure.

Autoimmune Inflammatory Processes

IgM and anti-CCP autoantibodies are proteins produced by the immune system in response to a perceived threat —which may be the result of an aberrant immune response of the organism against its own cells and tissues (autoimmune inflammatory processes). IgM and anti-CCP levels are, despite their co-occurence, only weakly correlated with each other (0.2 ≤ r ≤ 0.5) and have been found to vary with the structure of the antigen, its dose and route of entry, as well as with the host’s genetic predisposition. The antibodies by themselves (or in combination) are neither a necessary nor a sufficient condition of RA, and the respective levels are not normally distributed.

Molecular-Genetic Approach

Since the so-called "natural" antibody IgM in normal serum is often found to bind to specific antigens, even in the absence of prior immunization, and the formation of chronically elevated levels develops years before the first clinical symptoms occur [Nielen et al. 2006], elevated IgM levels may well be related to the patients’ genetically predisposed aberrancy of inflammatory response system, and may even be related to autoimmune diseases in general. The pathogenesis of these diseases, however, is insufficiently understood, also because the question of autoantibody appearance prior to chronic inflammation —indicating an antibody-driven inflammatory process— has not yet been answered on the basis of empirical data. We addressed the questions of (1) the extent to which the observed variation in IgM levels can be explained through genetic factors; (2) whether there exists a configuration of genomic loci that allows one to predict individual IgM levels from genotypes at a sufficiently high sensitivity and specificity; and (3) whether these predictors apply to the sample as a whole or only for smaller subsets.

Study Population

Our study comprised 1,042 subjects (511 nuclear families) ascertained through an index case with a clinical diagnosis of rheumatoid arthritis. As IgM levels ?as all other Immunoglobulins? are not normally distributed in the general population, we found the following empirical prevalences: 647 subjects were classified as having "normal" IgM levels, 257 subjects as having slightly elevated yet "low" IgM levels, and 138 subjects as having significantly "elevated" IgM levels. All subjets were genotyped for 5'728 SNPs of a 0.4 Mb genome scan.

pricipal components
Fig. 1: Projection of 1,042 subjects onto the plane defined by the 2 largest eigenvectors of a genetic vector space spanned by 16 polymorphic markers. The projections revealed clear differences on the genotype level between IgM-related groups: circles designate unaffected subjects (0 ≤ IgM < 13.5; n = 647), triangles subjects with low IgM levels (13.5 ≤ IgM < 50; n = 257), and squares subjects with elevated IgM levels (n = 138)).
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